Summary of the project
Ciliopathies are a large group of rare and severe genetic diseases caused by dysfunction of the primary cilium, a microtubule-based cell surface antenna that controls key signaling output required during development and tissue homeostasis. Cilium dysfunction leads to complex disorders with high genetic heterogeneity and overlapping phenotypes. Despite the broad clinical spectrum, chronic kidney disease (CKD) leading to end stage kidney disease (ESKD) is a common cause of morbidity across ciliopathies. Currently, the only available standard of care for CKD is based on dialysis and transplantation.
Renal ciliopathies represent a main cause of ESKD during childhood and despite the identification of more than 40 causative genes, it remains difficult to predict the severity of the disease as well as the risk of appearance (if not present at diagnosis) and the rate of progression of renal failure. TheRaCil therefore aims:
- To improve diagnosis and prognosis of at risk pediatric renal ciliopathy patients
- To implement therapeutic approaches aimed at targeting shared pathological pathways, at modifying mRNA targets of the causative or modifier genes by antisense oligonucleotides and by the repurposing of available molecules
These goals will be achieved through the federation of our unique databases of pediatric renal ciliopathies cases available across Europe, which will allow a better stratification of patients, the identification of modifier genes and markers of disease progression. Bioinformatics approaches will be used to integrate patients’ biological and genetic data as well as multi-omics and functional analyses from patients samples and preclinical models. These analyses should lead to the identification of shared targetable pathological pathways as well as of patients eligible for the identified new therapeutic approaches which will be evaluated in robust preclinical models
Work packages
WP 1
Data integration and clustering for predictive signatures
Objectives :
- Integrate the data available at each site in a hybrid federated/centralized manner and define data exchange formats
- Deliver a common data model to the ciliopathy community
- Exploit state-of-the-art database infrastructure for subsequent biostatistical and bioinformatic analyses required in WP3
- Provide a disease model (pathways, drug targets, variants) through machine learning trained on these data
- Apply the above to a patient population to achieve relevant patient clustering and identify patients eligible to the trials designed in WP7
WP 2
Molecular signatures and mechanistic principles for classification and therapy
Objectives :
- Decipher the molecular signatures and disturbed signaling pathways in disease conditions and how they can be modified by therapeutic interventions
- Understand how therapeutic interventions modify the identified disturbed ciliopathy protein modules and the composition of primary cilia
- Investigate the effect of candidate therapies on individual renal cell populations, cell metabolism, and extracellular vesicle release
- Validate and select targetable pathways, disease modifiers and interventions for further preclinical studies
WP 3
Patient Eligibility to treatment : prognostic tools and biomarkers
Objectives :
- Identify biomarkers of kidney disease onset and progression
- Validate genetic modifiers of disease severity
- Generate a predictive model for clinical applications
WP 4
Advanced Therapeutic strategies suitable for clinical use
Objectives :
- Prioritize advanced lead molecules in robust models recapitulating NPH/ARPKD clinical features
- Complete the pharmacological target product profile assessment of the most advanced EP2 agonist
- Improve therapeutic modalities with ASO specifically for use in renal ciliopathies
WP 5
Patient involvement and patient Centered Outcomes
Objectives :
- Identify, define and prioritize standardized PROMs for future clinical trials in ARPKD, NPH and BBS
- Improve identification of trial-eligible renal ciliopathy patients by assessing access and barriers to genetic testing
- Monitor the use and access of patients’ data
WP 6
Coordination and Management
Objectives :
- Monitor the project progress in terms of technical and administrative coordination among all partners
- Provide timely and efficient organizational and financial coordination to meet contractual requirements and commitments.
WP 7
Dissemination, communication and exploitation
Objectives :
- Engage and disseminate the results of the project widely to stakeholders
- Communicate about the project to the general public and potential stakeholders
- Align knowledge and results arising from the project with partner interests, market and regulatory needs and manage intellectual property to produce plans and agreements for post-project exploitation
WP 8
Ethics Requirements
Objectives :
- Give advice and guidance to all partners in order to ensure protection of the rights and interests of all those affected by the research
- Give advice and guidance to all partners in order to ensure respect for fundamental EU values and human rights
- Verify compliance with existing regulations
